Most pathogens in humans are Gram-positive organisms. One important member of the Gram-positive pathogens is S. aureus. About 20% of the population is a long-term carrier of S. aureus. S. aureus can cause a range of illnesses from minor skin infections, such as pimples, impetigo, boils, cellulitis folliculitis, furuncles, carbuncles, scalded skin syndrome, atopic dermatitis, and abscesses, to life-threatening diseases such as pneumonia, meningitis, osteomyelitis, endocarditis, and septicemia. S. aureus is capable of infecting all kinds of organs and tissues. S. aureus infections occur in immunocompetent as well as immune compromised people. About 50% of the infections in US intensive care units are caused by this pathogen. Three hundred thousand S. aureus infections per year, resulting in 12,000 deaths, are reported in the US (see, e.g., Moran et al., 2006, NEJM 355, 666-674).
S. aureus strains produce many secreted toxins important for virulence. One important virulence factor in the pathogenesis of S. aureus infection is alpha-toxin. Alpha-toxin is a member of a family of bacterial cytotoxins that is secreted by S. aureus and is capable of inserting into the cell membrane of a multitude of eukaryotic cells. The protein is secreted as a monomer; however, it assembles into a ring structure on the surface of eukaryotic cells. The assembled toxin inserts into the host cell membrane, forming a pore that contributes to cellular injury and death by disrupting the integrity of the membrane. Several biochemical studies have defined the amino acid residues within the alpha-toxin monomer that facilitate binding to the host cell, ring formation and host cell lysis. Recent work investigated the impact of alpha-toxin antibodies on the outcome of pneumonia (Bubeck Wardenburg and Schneewind, 2008, J. Exp. Med. 205:287-294; Ragle and Bubeck Wardenburg, 2009, Infect. Immun. 77:2712-2718). It has been reported that passive immunization with monoclonal antibodies to the N-terminus of alpha-toxin substantially reduced mortality in a mouse model for S. aureus pneumonia (Ragle and Bubeck Wardenburg, 2009, Infect. Immun. 77:2712-2718).
The clinical complexity of S. aureus infection and the fact that there is no single virulence factor central to the progression of all disease manifestations pose a challenge for development of therapeutics. There remains a need in the art for compositions and methods for preventing and/or treating S. aureus infection, as well as the attenuation or amelioration of the secondary effects of such an infection.